Surface treatment of biomedical devices

ABSTRACT

A surface modified biomedical device is provided comprising a biomedical device having a coating on at least a portion thereof, the coating comprising a polymer or copolymer having one or more repeating units of the formula: 
     
       
         
         
             
             
         
       
     
     wherein R independently is a C 2 -C 20  hydrocarbon radical and n is an integer of 2 to 5000.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 11/874,427filed Nov. 20, 2007 which claims benefit of U.S. Provisional Appln. No.60/870,172, which was filed Dec. 15, 2006.

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention is directed to the surface treatment of biomedicaldevices including ophthalmic lenses, stents, implants and catheters toincrease their wettability.

2. Description of Related Art

Medical devices such as ophthalmic lenses made from, for example,silicone-containing materials, have been investigated for a number ofyears. Such materials can generally be subdivided into two majorclasses, namely hydrogels and non-hydrogels. Hydrogels can absorb andretain water in an equilibrium state, whereas non-hydrogels do notabsorb appreciable amounts of water. Regardless of their water content,both hydrogel and non-hydrogel silicone medical devices tend to haverelatively hydrophobic, non-wettable surfaces that have a high affinityfor lipids. This problem is of particular concern with contact lenses.

Those skilled in the art have long recognized the need for modifying thesurface of such silicone contact lenses so that they are compatible withthe eye. It is known that increased hydrophilicity of the contact lenssurface improves the wettability of the contact lenses. This, in turn,is associated with improved wear comfort of contact lenses.Additionally, the surface of the lens can affect the lens'ssusceptibility to deposition, particularly the deposition of proteinsand lipids resulting from tear fluid during lens wear. Accumulateddeposition can cause eye discomfort or even inflammation. In the case ofextended wear lenses (i.e., lenses used without daily removal of thelens before sleep), the surface is especially important, since extendedwear lenses must be designed for high standards of comfort andbiocompatibility over an extended period of time.

Silicone lenses have been subjected to plasma surface treatment toimprove their surface properties, e.g., surfaces have been rendered morehydrophilic, deposit resistant, scratch-resistant, or otherwisemodified. Examples of previously disclosed plasma surface treatmentsinclude subjecting the surface of a contact lens to a plasma containingan inert gas or oxygen (see, for example, U.S. Pat. Nos. 4,055,378;4,122,942; and 4,214,014); various hydrocarbon monomers (see, forexample, U.S. Pat. No. 4,143,949); and combinations of oxidizing agentsand hydrocarbons such as water and ethanol (see, for example, WO95/04609 and U.S. Pat. No. 4,632,844). U.S. Pat. No. 4,312,575 disclosesa process for providing a barrier coating on a silicone or polyurethanelens by subjecting the lens to an electrical glow discharge (plasma)process conducted by first subjecting the lens to a hydrocarbonatmosphere followed by subjecting the lens to oxygen during flowdischarge, thereby increasing the hydrophilicity of the lens surface.

U.S. Pat. Nos. 4,168,112, 4,321,261 and 4,436,730 disclose methods fortreating a charged contact lens surface with an oppositely charged ionicpolymer to form a polyelectrolyte complex on the lens surface thatimproves wettability.

U.S. Pat. No. 4,287,175 discloses a method of wetting a contact lensthat comprises inserting a water-soluble solid polymer into thecul-de-sac of the eye. The disclosed polymers include cellulosederivatives, acrylates and natural products such as gelatin, pectins andstarch derivatives.

U.S. Pat. No. 5,397,848 discloses a method of incorporating hydrophilicconstituents into silicone polymer materials for use in contact andintra-ocular lenses.

U.S. Pat. Nos. 5,700,559 and 5,807,636 disclose hydrophilic articles(e.g., contact lenses) comprising a substrate, an ionic polymeric layeron the substrate and a disordered polyelectrolyte coating ionicallybonded to the polymeric layer.

U.S. Pat. No. 5,705,583 discloses biocompatible polymeric surfacecoatings. The polymeric surface coatings disclosed include coatingssynthesized from monomers bearing a center of positive charge, includingcationic and zwitterionic monomers.

European Patent Application No. EP 0 963 761 A1 discloses biomedicaldevices with coatings that are said to be stable, hydrophilic andantimicrobial, and which are formed using a coupling agent to bond acarboxyl-containing hydrophilic coating to the surface of the devices byester or amide linkages.

U.S. Pat. No. 6,428,839 discloses a method for improving the wettabilityof a medical device which includes the steps of (a) providing a medicaldevice formed from a monomer mixture comprising a hydrophilic monomerand a silicone-containing monomer; and (b) contacting a surface of themedical device with a solution including a polymer or copolymer of(meth)acrylic acid.

Typically, a medical device such as a contact lens is exposed to anaqueous environment having a pH in the range from 6.5 to 8.0 duringstorage in a package and during wear. A problem associated with coatingsformed from a polymer or copolymer of (meth)acrylic acid is that duringuse of the contact lens in this pH environment, these polymers arehighly ionized and have little surface activity. Therefore, the coatingcan be removed from the lens relatively easily thereby exposing the lenssurface and resulting in a reduction in wetting and lubricity.

Accordingly, it would be desirable to provide improved biomedicaldevices such as a silicone hydrogel contact lens with an opticallyclear, hydrophilic surface film that will not only exhibit improvedwettability, but which will generally allow the use of a siliconehydrogel contact lens in the human eye for an extended period of time.In the case of a silicone hydrogel lens for extended wear, it would bedesirable to provide a contact lens with a surface that is also highlypermeable to oxygen and water. Such a surface treated lens would becomfortable to wear in actual use and would allow for the extended wearof the lens without irritation or other adverse effects to the cornea.

SUMMARY OF THE INVENTION

In accordance with one embodiment of the present invention, a method forimproving the wettability of a biomedical device is provided comprisingthe step of contacting a surface of the biomedical device with acomposition comprising a polymer or copolymer having one or morerepeating units of the formula:

wherein R independently is a C₂-C₂₀ hydrocarbon radical and n is aninteger of 2 to 5000.

In accordance with a second embodiment of the present invention, amethod for improving the wettability of a biomedical device is providedcomprising the step of contacting a surface of a biomedical deviceformed from a monomeric mixture comprising a hydrophilic monomer and asilicone-containing monomer with a composition comprising a polymer orcopolymer having one or more repeating units of the formula:

wherein R independently is a C₂-C₂₀ hydrocarbon radical and n is aninteger of 2 to 5000.

In accordance with a third embodiment of the present invention, asurface modified biomedical device is provided comprising a biomedicaldevice having a coating on a surface thereof, the coating comprising apolymer or copolymer having one or more repeating units of the formula:

wherein R independently is a C₂-C₂₀ hydrocarbon radical and n is aninteger of 2 to 5000.

In accordance with a fourth embodiment of the present invention, asurface modified biomedical device is provided comprising a biomedicaldevice having a coating on a surface thereof, the coating comprising apolymer or copolymer obtained from the polymerization orcopolymerization of a monomeric mixture comprising one or more C₂-C₂₀straight chain, branched, and cyclic 2-alpha-alkyl acrylic acids.

In accordance with a fifth embodiment of the present invention, a methodof forming a surface modified biomedical device is provided comprising(a) providing a biomedical device; and (b) coating a surface of thebiomedical device with a coating composition comprising a polymer orcopolymer having one or more repeating units of the formula:

wherein R independently is a C₂-C₂₀ hydrocarbon radical and n is aninteger of 2 to 5000.

In accordance with a sixth embodiment of the present invention, a methodis provided comprising:

(a) immersing an ophthalmic device in a solution comprising a polymer orcopolymer having one or more repeating units of the formula:

wherein R independently is a C₂-C₂₀ hydrocarbon radical and n is aninteger of 2 to 5000, wherein the solution has an osmolality of at leastabout 200 mOsm/kg and a pH in the range of about 6 to about 9;

(b) packaging the solution and the device in a manner preventingcontamination of the device by microorganisms; and

(c) sterilizing the packaged solution and device.

In accordance with a seventh embodiment of the present invention, apackaging system for the storage of an ophthalmic device is providedcomprising a sealed container containing one or more unused ophthalmicdevices immersed in an aqueous packaging solution comprising a polymeror copolymer having one or more repeating units of the formula:

wherein R independently is a C₂-C₂₀ hydrocarbon radical and n is aninteger of 2 to 5000, wherein the solution has an osmolality of at leastabout 200 mOsm/kg and a pH in the range of about 6 to about 9 and isheat sterilized.

In accordance with an eighth embodiment of the present invention, apackaging system for the storage of an ophthalmic device is providedcomprising:

(a) an aqueous packaging solution comprising a polymer or copolymerhaving one or more repeating units of the formula:

wherein R independently is a C₂-C₂₀ hydrocarbon radical and n is aninteger of 2 to 5000, wherein the solution has an osmolality of at leastabout 200 mOsm/kg and a pH in the range of about 6 to about 9;

(b) at least one ophthalmic device; and

(c) a container for holding the solution and ophthalmic devicesufficient to preserve the sterility of the solution and ophthalmicdevice, wherein the solution does not contain an effective disinfectingamount of a disinfecting agent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation showing the conformationaltransition of the substituent group at the 2-position of a series ofpoly(carboxylic acid)s.

FIG. 2 is a graphical representation showing the Carbon 1s (C1s)photoelectron region of the X-ray Photoelectron Spectrometer (XPS)spectra of a series of poly(carboxylic acid)s.

FIG. 3 is a graphical representation showing the Oxygen 1s (O1s)photoelectron region of the XPS spectra of a series of differentpoly(carboxylic acid)s.

FIG. 4 is a graphical representation showing the percent siliconeconcentration of the XPS spectra of a series of poly(carboxylic acid)s.

FIG. 5 is a graphical representation showing the contact angle data of aseries of poly(carboxylic acid)s.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides a surface modified biomedical device suchas a contact lens, e.g., a silicone hydrogel contact lens, which has acoating on at least a portion thereon. The coating compositionadvantageously improves the hydrophilicity and lipid resistance of thebiomedical device by forming a coating thereon.

The preferred biomedical devices for use herein are ophthalmic devices,more preferably contact lenses, and most preferably contact lenses madefrom silicone hydrogels. The biomedical devices such as wettablesilicone-based hydrogel formulations are coated with the coatingcomposition described herein to render a lubricious, stable, highlywettable poly(carboxylic acid) containing surface coating on thebiomedical device.

As used herein, the terms “lens” and “opthalmic device” refer to devicesthat reside in or on the eye. These devices can provide opticalcorrection, wound care, drug delivery, diagnostic functionality orcosmetic enhancement or any combination of these properties.Representative examples of such devices include, but are not limited to,soft contact lenses, e.g., soft, hydrogel lens, soft, non-hydrogel lensand the like, hard contact lenses, e.g., hard, gas permeable lensmaterials and the like, intraocular lenses, overlay lenses, ocularinserts, optical inserts and the like. As is understood by one skilledin the art, a lens is considered to be “soft” if it can be folded backupon itself without breaking. Any material known to produce a biomedicaldevice including an ophthalmic device can be used herein.

It is particularly useful to employ biocompatible materials hereinincluding both soft and rigid materials commonly used for opthalmiclenses, including contact lenses. The preferred substrates are hydrogelmaterials, including silicone hydrogel materials. Particularly preferredmaterials include vinyl functionalized polydimethylsiloxanescopolymerized with hydrophilic monomers as well as fluorinatedmethacrylates and methacrylate functionalized fluorinated polyethyleneoxides copolymerized with hydrophilic monomers. Representative examplesof substrate materials for use herein include those disclosed in U.S.Pat. Nos. 5,310,779; 5,387,662; 5,449,729; 5,512,205; 5,610,252;5,616,757; 5,708,094; 5,710,302; 5,714,557 and 5,908,906, the contentsof which are incorporated by reference herein.

A wide variety of materials can be used herein, and silicone hydrogelcontact lens materials are particularly preferred. Hydrogels in generalare a well known class of materials that comprise hydrated, cross-linkedpolymeric systems containing water in an equilibrium state. Siliconehydrogels generally have a water content greater than about 5 weightpercent and more commonly between about 10 to about 80 weight percent.Such materials are usually prepared by polymerizing a mixture containingat least one silicone-containing monomer and at least one hydrophilicmonomer. Typically, either the silicone-containing monomer or thehydrophilic monomer functions as a crosslinking agent (a crosslinkerbeing defined as a monomer having multiple polymerizablefunctionalities) or a separate crosslinker may be employed. Applicablesilicone-containing monomeric units for use in the formation of siliconehydrogels are well known in the art and numerous examples are providedin U.S. Pat. Nos. 4,136,250; 4,153,641; 4,740,533; 5,034,461; 5,070,215;5,260,000; 5,310,779; and 5,358,995.

Representative examples of applicable silicon-containing monomeric unitsinclude bulky polysiloxanylalkyl(meth)acrylic monomers. An example of abulky polysiloxanylalkyl(meth)acrylic monomer is represented by thestructure of Formula I:

wherein X denotes —O— or —NR—; each R¹ independently denotes hydrogen ormethyl; each R² independently denotes a lower alkyl radical, phenylradical or a group represented by

wherein each R^(2′) independently denotes a lower alkyl or phenylradical; and h is 1 to 10.

Examples of bulky monomers are methacryloxypropyltris(trimethyl-siloxy)silane or tris(trimethylsiloxy)silylpropylmethacrylate, sometimes referred to as TRIS andtris(trimethylsiloxy)silylpropyl vinyl carbamate, sometimes referred toas TRIS-VC and the like.

Such bulky monomers may be copolymerized with a silicone macromonomer,which is a poly(organosiloxane) capped with an unsaturated group at twoor more ends of the molecule. U.S. Pat. No. 4,153,641 discloses, forexample, various unsaturated groups such as acryloxy or methacryloxygroups.

Another class of representative silicone-containing monomers includes,but is not limited to, silicone-containing vinyl carbonate or vinylcarbamate monomers such as, for example,1,3-bis[4-vinyloxycarbonyloxy)but-1-yl]tetramethyl-disiloxane;3-(trimethylsilyl)propyl vinyl carbonate;3-(vinyloxycarbonylthio)propyl-[tris(trimethylsiloxy)silane];3-[tris(trimethylsiloxy)silyl]propyl vinyl carbamate;3-[tris(trimethylsiloxy)silyl]propyl allyl carbamate;3-[tris(trimethylsiloxy)silyl]propyl vinyl carbonate;t-butyldimethylsiloxyethyl vinyl carbonate; trimethylsilylethyl vinylcarbonate; trimethylsilylmethyl vinyl carbonate and the like andmixtures thereof.

Another class of silicon-containing monomers includespolyurethane-polysiloxane macromonomers (also sometimes referred to asprepolymers), which may have hard-soft-hard blocks like traditionalurethane elastomers. They may be end-capped with a hydrophilic monomersuch as HEMA. Examples of such silicone urethanes are disclosed in avariety or publications, including Lai, Yu-Chin, “The Role of BulkyPolysiloxanylalkyl Methacryates in Polyurethane-Polysiloxane Hydrogels,”Journal of Applied Polymer Science, Vol. 60, 1193-1199 (1996). PCTPublished Application No. WO 96/31792 discloses examples of suchmonomers, which disclosure is hereby incorporated by reference in itsentirety. Further examples of silicone urethane monomers are representedby Formulae II and III:

E(*D*A*D*G)_(a)*D*A*D*E′; or  (II)

E(*D*G*D*A)_(a)*D*A*D*E′; or  (III)

wherein:

D independently denotes an alkyl diradical, an alkyl cycloalkyldiradical, a cycloalkyl diradical, an aryl diradical or an alkylaryldiradical having 6 to about 30 carbon atoms;

G independently denotes an alkyl diradical, a cycloalkyl diradical, analkyl cycloalkyl diradical, an aryl diradical or an alkylaryl diradicalhaving 1 to about 40 carbon atoms and which may contain ether, thio oramine linkages in the main chain;

* denotes a urethane or ureido linkage;

a is at least 1;

A independently denotes a divalent polymeric radical of Formula IV:

wherein each R^(s) independently denotes an alkyl or fluoro-substitutedalkyl group having 1 to about 10 carbon atoms which may contain etherlinkages between the carbon atoms; m′ is at least 1; and p is a numberthat provides a moiety weight of about 400 to about 10,000;

each of E and E′ independently denotes a polymerizable unsaturatedorganic radical represented by Formula V:

wherein: R³ is hydrogen or methyl;R⁴ is hydrogen, an alkyl radical having 1 to 6 carbon atoms, or a—CO—Y—R⁶ radical wherein Y is —O—, —S— or —NH—;R⁵ is a divalent alkylene radical having 1 to about 10 carbon atoms;R⁶ is a alkyl radical having 1 to about 12 carbon atoms;X denotes —CO— or —OCO—;Z denotes —O— or —NH—;Ar denotes an aromatic radical having about 6 to about 30 carbon atoms;w is 0 to 6; x is 0 or 1; y is 0 or 1; and z is 0 or 1.

A preferred silicone-containing urethane monomer is represented byFormula

wherein m is at least 1 and is preferably 3 or 4, a is at least 1 andpreferably is 1, p is a number which provides a moiety weight of about400 to about 10,000 and is preferably at least about 30, R⁷ is adiradical of a diisocyanate after removal of the isocyanate group, suchas the diradical of isophorone diisocyanate, and each E″ is a grouprepresented by:

In another embodiment of the present invention, a silicone hydrogelmaterial comprises (in bulk, that is, in the monomer mixture that iscopolymerized) about 5 to about 50 percent, and preferably about 10 toabout 25, by weight of one or more silicone macromonomers, about 5 toabout 75 percent, and preferably about 30 to about 60 percent, by weightof one or more polysiloxanylalkyl (meth)acrylic monomers, and about 10to about 50 percent, and preferably about 20 to about 40 percent, byweight of a hydrophilic monomer. In general, the silicone macromonomeris a poly(organosiloxane) capped with an unsaturated group at two ormore ends of the molecule. In addition to the end groups in the abovestructural formulas, U.S. Pat. No. 4,153,641 discloses additionalunsaturated groups, including acryloxy or methacryloxy.Fumarate-containing materials such as those disclosed in U.S. Pat. Nos.5,310,779; 5,449,729 and 5,512,205 are also useful substrates inaccordance with the invention. The silane macromonomer may be asilicon-containing vinyl carbonate or vinyl carbamate or apolyurethane-polysiloxane having one or more hard-soft-hard blocks andend-capped with a hydrophilic monomer.

Suitable hydrophilic monomers include, but are not limited to, amidessuch as dimethylacrylamide and dimethylmethacrylamide, cyclic lactamssuch as N-vinyl-2-pyrrolidone and poly(alkene glycols) functionalizedwith polymerizable groups. Examples of useful functionalized poly(alkeneglycols) include poly(diethylene glycols) of varying chain lengthcontaining monomethacrylate or dimethacrylate end caps. In oneembodiment, the poly(alkene glycol) polymer can contain at least twoalkene glycol monomeric units. Still further examples are thehydrophilic vinyl carbonate or vinyl carbamate monomers disclosed inU.S. Pat. No. 5,070,215, and the hydrophilic oxazolone monomersdisclosed in U.S. Pat. No. 4,910,277. Other suitable hydrophilicmonomers will be apparent to one skilled in the art.

Another class of representative silicone-containing monomers includesfluorinated monomers. Such monomers have been used in the formation offluorosilicone hydrogels to reduce the accumulation of deposits oncontact lenses made therefrom, as disclosed in, for example, U.S. Pat.Nos. 4,954,587; 5,010,141 and 5,079,319. The use of silicone-containingmonomers having certain fluorinated side groups, i.e., —(CF₂)—H, havebeen found to improve compatibility between the hydrophilic andsilicone-containing monomeric units. See, e.g., U.S. Pat. Nos. 5,321,108and 5,387,662.

The above silicone materials are merely exemplary, and other materialsfor use as substrates that can benefit by being coated with thehydrophilic coating composition according to the present invention andhave been disclosed in various publications and are being continuouslydeveloped for use in contact lenses and other medical devices can alsobe used.

Contact lenses for application of the present invention can bemanufactured employing various conventional techniques, to yield ashaped article having the desired posterior and anterior lens surfaces.Spincasting methods are disclosed in U.S. Pat. Nos. 3,408,429 and3,660,545; and static casting methods are disclosed in U.S. Pat. Nos.4,113,224, 4,197,266 and 5,271,876. Curing of the monomeric mixture maybe followed by a machining operation in order to provide a contact lenshaving a desired final configuration. As an example, U.S. Pat. No.4,555,732 discloses a process in which an excess of a monomeric mixtureis cured by spincasting in a mold to form a shaped article having ananterior lens surface and a relatively large thickness. The posteriorsurface of the cured spincast article is subsequently lathe cut toprovide a contact lens having the desired thickness and posterior lenssurface. Further machining operations may follow the lathe cutting ofthe lens surface, for example, edge-finishing operations.

Typically, an organic diluent is included in the initial monomericmixture in order to minimize phase separation of polymerized productsproduced by polymerization of the monomeric mixture and to lower theglass transition temperature of the reacting polymeric mixture, whichallows for a more efficient curing process and ultimately results in amore uniformly polymerized product. Sufficient uniformity of the initialmonomeric mixture and the polymerized product is of particularimportance for silicone hydrogels, primarily due to the inclusion ofsilicone-containing monomers which may tend to separate from thehydrophilic comonomer. Suitable organic diluents include, for example,monohydric alcohols such as C₆-C₁₀ straight-chained aliphatic monohydricalcohols, e.g., n-hexanol and n-nonanol; diols such as ethylene glycol;polyols such as glycerin; ethers such as diethylene glycol monoethylether; ketones such as methyl ethyl ketone; esters such as methylenanthate; and hydrocarbons such as toluene. Preferably, the organicdiluent is sufficiently volatile to facilitate its removal from a curedarticle by evaporation at or near ambient pressure. Generally, thediluent may be included at about 5 to about 60 percent by weight of themonomeric mixture, with about 10 to about 50 percent by weight beingespecially preferred. If necessary, the cured lens may be subjected tosolvent removal, which can be accomplished by evaporation at or nearambient pressure or under vacuum. An elevated temperature can beemployed to shorten the time necessary to evaporate the diluent.

Following removal of the organic diluent, the lens can then be subjectedto mold release and optional machining operations. The machining stepincludes, for example, buffing or polishing a lens edge and/or surface.Generally, such machining processes may be performed before or after thearticle is released from a mold part. As an example, the lens may be dryreleased from the mold by employing vacuum tweezers to lift the lensfrom the mold.

Next, the biomedical devices are contacted with a coating composition ofthis invention. The devices may either be unhydrated or prehydrated inwater or aqueous solution. The coating composition of this inventioncontains a polymer or copolymer having one or more repeating units ofthe formula:

wherein R independently is a C₂-C₂₀ hydrocarbon radical and preferably aC₂-C₆ hydrocarbon radical and n is an integer of 2 to 5000, preferably 2to about 2000 and most preferably from about 10 to about 1000. SuitableC₂-C₂₀ hydrocarbon radicals include, by way of example, straight chainor branched alkyl groups, cycloalkyl groups, cycloalkyl alkyl groups,cycloalkenyl groups, aryl groups, arylalkyl groups and the like. Thecopolymers can be random, block or grafted copolymers. The polymers orcopolymers can have a weight average molecular weight ranging from about500 to about 1,000,000 and preferably from about 10,000 to about500,000.

Representative examples of alkyl groups for use herein include, by wayof example, a straight or branched hydrocarbon chain radical containingcarbon and hydrogen atoms of from 2 to 20 and preferably 2 to 6 carbonatoms with or without unsaturation, to the rest of the molecule, e.g.,ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, etc., andthe like.

Representative examples of cycloalkyl groups for use herein include, byway of example, a substituted or unsubstituted non-aromatic mono ormulticyclic ring system of from 3 to 20 and preferably about 3 to about6 carbon atoms such as, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

Representative examples of cycloalkylalkyl groups for use hereininclude, by way of example, a substituted or unsubstituted cyclicring-containing radical containing from from 3 to 20 and preferablyabout 3 to 6 carbon atoms directly attached to an alkyl group which isthen attached to the main structure of the monomer at any carbon fromthe alkyl group that results in the creation of a stable structure suchas, for example, cyclopropylmethyl, cyclobutylethyl, and the like.

Representative examples of cycloalkenyl groups for use herein include,by way of example, a substituted or unsubstituted cyclic ring-containingradical containing from 3 to 20 and preferably about 3 to 6 carbon atomswith at least one carbon-carbon double bond such as, for example,cyclopropenyl, cyclobutenyl, cyclopentenyl and the like.

Representative examples of aryl groups for use herein include, by way ofexample, a substituted or unsubstituted aromatic-containing radicalhaving from 5 to 20 and preferably 5 to 7 carbon atoms such as, forexample, phenyl, and the like.

Representative examples of arylalkyl groups for use herein include, byway of example, a substituted or unsubstituted aryl group as definedabove directly bonded to an alkyl group as defined above, e.g.,—CH₂C₆H₅, —C₂H₅C₆H₅ and the like.

In general, the polymer or copolymer can be obtained from thepolymerization or copolymerization of a monomeric mixture comprising oneor more C₂-C₂₀ 2-alpha-hydrocarbon substituted acrylic acids. Preferredhydrocarbon substituted acrylic acid monomers for use in preparing thepolymeric materials include ethylacrylic acid (EAA), propylacrylic acid(PAA), butylacrylic acid (BAA) and mixtures thereof.

Copolymers of these monomers by themselves or other monomers such asacrylic acid can be used. Representative examples of additional monomersinclude hydrophilic monomers such as acrylamides, e.g.,N,N-dimethylacrylamide (DMA) and the like; vinyl lactams, e.g.,N-vinylpyrrolidinone (NVP) and the like; (meth)acrylated poly(alkyleneoxides), e.g., methoxypolyoxyethylene methacrylates and the like,hydroxyalkyl (meth)acrylates, e.g., hydroxyethyl methacrylate (HEMA) andthe like, epoxy-functional monomers, e.g., glycidyl methacrylate (GMA)and the like and mixtures thereof.

The polymers or copolymers can be synthesized in any manner known perse, from the corresponding monomers (the term monomer herein alsoincluding a macromer) by a polymerization reaction customary to theperson skilled in the art. For example, in one embodiment, the polymersor copolymers can be obtained by at least (a) mixing the one or moremonomers together; (b) adding a polymerization initiator; (c) subjectingthe monomer/initiator mixture to thermal energy or a source ofultraviolet or other light and curing the mixture. Typicalpolymerization initiators include free-radical-generating polymerizationinitiators of the type illustrated by acetyl peroxide, lauroyl peroxide,decanoyl peroxide, coprylyl peroxide, benzoyl peroxide, tertiary butylperoxypivalate, sodium percarbonate, tertiary butyl peroctoate, andazobis-isobutyronitrile (AIBN). Ultraviolet free-radical initiatorsillustrated by diethoxyacetophenone can also be used. The curing processwill of course depend upon the initiator used and the physicalcharacteristics of the comonomer mixture such as viscosity. In anyevent, the level of initiator employed may vary within the range ofabout 0.01 to about 2 weight percent of the mixture of monomers.Usually, a mixture of the above-mentioned monomers is warmed withaddition of a free-radical former.

In an alternative embodiment, block copolymers can be synthesized bycontrolled free radical techniques known in the art to produce asegmented block copolymer.

Polymerization of the monomeric mixture to form the polymers orcopolymers can be carried out in the presence of a solvent. Suitablesolvents are in principle all solvents which dissolve the monomericmixture used such as, for example, water, alcohols such as loweralkanols, e.g., methanol, methanol and the like; carboxamides such asdimethylformamide and the like; dipolar aprotic solvents such asdimethyl sulfoxide and the like; ketones such as acetone, methyl ethylketone, cyclohexanone, and the like; aliphatic or aromatic hydrocarbonssuch as toluene, xylene, n-hexane and the like; ethers such as THF,dimethoxyethane, dioxane and the like; halogenated hydrocarbons such astrichloroethane and the like, and also mixtures of suitable solvents,for example mixtures of water and an alcohol, e.g., a water/methanol orwater/ethanol mixture, and the like.

The coating can be formed on the biomedical device by conventionaltechniques, for example, immersion, dip coating, spray coating,electrostatic coating and the like. For example, in one embodiment, asurface of a biomedical device can be contacted with a coatingcomposition of this invention containing a polymer or copolymer formedfrom a monomeric mixture containing at least one C₂-C₂₀ hydrocarbonsubstituted acrylic acid monomer, and the polymer or copolymer forms acoating on the surface thereof. The biomedical device can be contactedwith the coating polymer in an aqueous or organic solvent at atemperature and time period sufficient to form the coating on thesurface of the device.

Alternatively, a biomedical device such as a contact lens can be coatedby immersing the biomedical device in a packaging solution containingthe polymer or copolymers described hereinabove. In one embodiment, thesolution is a packaging solution for storing the lens. The packagingsolutions according to the present invention are physiologicallycompatible. Specifically, the solution must be “ophthalmically safe” foruse with a lens such as a contact lens, meaning that a contact lenstreated with the solution is generally suitable and safe for directplacement on the eye without rinsing, that is, the solution is safe andcomfortable for daily contact with the eye via a contact lens that hasbeen wetted with the solution. An ophthalmically safe solution has atonicity and pH that is compatible with the eye and includes materials,and amounts thereof, that are non-cytotoxic according to ISO standardsand U.S. Food & Drug Administration (FDA) regulations. The polymer orcopolymer will ordinarily be present in the solution in an amountranging from about 10 ppm to about 10 wt. %, and preferably about 0.1wt. % to about 5 wt. %.

The solution of the present invention should also be sterile in that theabsence of microbial contaminants in the product prior to release mustbe statistically demonstrated to the degree necessary for such products.The liquid media useful in the present invention are selected to have nosubstantial detrimental effect on the lens being treated or cared forand to allow or even facilitate the present lens treatment ortreatments. The liquid media are preferably aqueous-based. Aparticularly useful aqueous liquid medium is that derived from saline,for example, a conventional saline solution or a conventional bufferedsaline solution.

The pH of the present solutions should be maintained within the range ofabout 6 to about 9, and preferably about 6.5 to about 7.8. Suitablebuffers may be added, such as boric acid, sodium borate, potassiumcitrate, citric acid, sodium bicarbonate, trimethamine, and variousmixed phosphate buffers (including combinations of Na₂ HPO₄, NaH₂ PO₄and KH₂ PO4) and mixtures thereof. Generally, buffers will be used inamounts ranging from about 0.05 to about 2.5 percent by weight, andpreferably from about 0.1 to about 1.5 percent by weight of thesolution.

Typically, the solutions of the present invention are also adjusted withtonicity agents, to approximate the osmotic pressure of normal lacrimalfluids which is equivalent to a 0.9 percent solution of sodium chlorideor 2.5 percent of glycerol solution. The solutions are madesubstantially isotonic with physiological saline used alone or incombination, otherwise if simply blended with sterile water and madehypotonic or made hypertonic the lenses will lose their desirableoptical parameters. Correspondingly, excess saline may result in theformation of a hypertonic solution which will cause stinging and eyeirritation.

Examples of suitable tonicity adjusting agents include, but are notlimited to, sodium and potassium chloride, dextrose, glycerin, calciumand magnesium chloride and the like and mixtures thereof. These agentsare typically used individually in amounts ranging from about 0.01 toabout 2.5% w/v and preferably from about 0.2 to about 1.5% w/v.Preferably, the tonicity agent will be employed in an amount to providea final osmotic value of at least about 200 mOsm/kg, preferably fromabout 200 to about 400 mOsm/kg, more preferably from about 250 to about350 mOsm/kg, and most preferably from about 280 to about 320 mOsm/kg.

If desired, one or more additional components can be included in thepackaging solution. Such additional component or components are chosento impart or provide at least one beneficial or desired property to thepackaging solution. Such additional components may be selected fromcomponents which are conventionally used in one or more ophthalmicdevice care compositions. Examples of such additional components includecleaning agents, wetting agents, nutrient agents, sequestering agents,viscosity builders, contact lens conditioning agents, antioxidants, andthe like and mixtures thereof. These additional components may each beincluded in the packaging solutions in an amount effective to impart orprovide the beneficial or desired property to the packaging solutions.For example, such additional components may be included in the packagingsolutions in amounts similar to the amounts of such components used inother, e.g., conventional, contact lens care products.

Useful sequestering agents include, but are not limited to, disodiumethylene diamine tetraacetate, alkali metal hexametaphosphate, citricacid, sodium citrate and the like and mixtures thereof.

Useful viscosity builders include, but are not limited to, hydroxyethylcellulose, hydroxymethyl cellulose, polyvinyl pyrrolidone, polyvinylalcohol and the like and mixtures thereof.

Useful antioxidants include, but are not limited to, sodiummetabisulfite, sodium thiosulfate, N-acetylcysteine, butylatedhydroxyanisole, butylated hydroxytoluene and the like and mixturesthereof.

The method of packaging and storing a biomedical device such as anophthalmic lens according to the present invention includes at leastpackaging an ophthalmic lens immersed in an aqueous ophthalmic-lenspackaging solution. The method may include immersing the lens in anaqueous packaging solution prior to delivery to the customer/wearer,directly following manufacture of the ophthalmic lens. Alternately, thepackaging and storing in the solution of the present invention may occurat an intermediate point before delivery to the ultimate customer(wearer) but following manufacture and transportation of the lens in adry state, wherein the dry lens is hydrated by immersing the lens in theophthalmic-lens packaging solution. Consequently, a package for deliveryto a customer may include a sealed container containing one or moreunused ophthalmic lenses immersed in an aqueous packaging solutionaccording to the present invention.

In one embodiment, the steps leading to the present ophthalmic lenspackaging system includes (1) molding an ophthalmic lens in a moldcomprising a posterior and anterior mold portion, (2) removing the lensfrom the mold and hydrating the lens, (3) introducing the packagingsolution with the C₂-C₂₀ hydrocarbon substituted acrylic acid polymer orcopolymer into the container with the lens supported therein, and (4)sealing the container. Preferably, the method also includes the step ofsterilizing the contents of the container. Sterilization may take placeprior to, or most conveniently after, sealing of the container and maybe effected by any suitable method known in the art, e.g., byautoclaving of the sealed container and its contents at temperatures ofabout 120° C. or higher.

In another embodiment, this invention comprises: (1) molding anophthalmic lens in a mold comprising a posterior and anterior moldportion, (2) removing the lens from the mold, and (3) introducing thelens and the solution with the C₂-C₂₀ hydrocarbon substituted acrylicacid polymer or copolymer into a container.

The following examples are provided to enable one skilled in the art topractice the invention and are merely illustrative of the invention. Theexamples should not be read as limiting the scope of the invention asdefined in the claims.

Example 1 Step I: Preparation of 2-Ethylacrylic acid

2-Ethylacrylic acid was prepared from diethyl ethylmalonate usingprocedures set forth in the literature (e.g., Ferrito et al., Macromol.Synth., 11, pp. 59-62 (1992)). Diethyl ethylmalonate (100 g, 0.53 mol)was added to a 1 L round bottom flask and stirred overnight with 700 mLof 1 M KOH in 95% ethanol. The ethanol was then removed with a rotaryevaporator and the residue was dissolved in a minimum amount of waterand acidified to a pH of 2.0 by slow addition of concentrated HCl. Theseparated oil (2-carboethoxybutyric acid) was taken up into diethylether (3×200 mL portions of ether in a reparatory funnel), dried overmagnesium sulfate and concentrated on a rotary evaporator. The crude2-carboethoxybutyric acid (84.9 g, 0.53 mol) was placed in a 1 L roundbottom flask and cooled to −5° C. Diethylamine (55 mL, 0.53 mol) wasthen added to the flask and an addition funnel containing 43.5 gformaline solution (0.54 mol) was added dropwise to the reaction mixturewhile allowing the solution to slowly warm to room temperature. Afterstirring for 24 hours, the addition funnel was replaced with a refluxcondenser and the reaction was warmed to 60° C. for 8 hours. Thereaction mixture was then cooled to 0° C. and concentrated sulfuric acidwas added slowly until evolution of gas ceases. The mixture wasextracted with three 200 mL portions of diethyl ether, dried overmagnesium sulfate, and concentrated on a rotary evaporator to obtain2-ethylacrylate. Crude 2-ethylacrylate (64.1 g, 0.5 mol) was placed in a1 L round bottom flask and 600 ml of 2M aqueous KOH was added. The flaskwas fitted with a reflux condenser and the reaction was refluxed for 20hours. The solution was allowed to cool to room temperature and wasacidified with 1N HCl to a pH of 2. The separated oil was extracted fourtimes with 700 mL of ether, dried over magnesium sulfate andconcentrated on a rotary evaporator. The yellow oil was vacuum distilled(bp 50° C./1 mm Hg) to yield pure, colorless 2-ethylacrylic acid (35 g).

Step II: Preparation of Poly(2-ethylacrylic acid)

Distilled 2-ethylacrylic acid was placed in ampules and subjected tofour freeze-degas-thaw cycles and sealed under vacuum. AIBN (from 0.1-5mol %) was added and the polymerizations was carried out in bulk at 64°C. for 24 hours. The resulting slurry was dissolved in methanol andprecipitated into diethyl ether. The precipitated polymer was collectedby filtration, dissolved in pH 9 phosphate buffer, and dialyzed againstwater for several days in cellulose dialysis tubing (MWCO=1000).

Example 2 Step I: Preparation of 2-Propylacrylic acid

2-Propylacrylic acid was prepared from diethyl propylmalonate by amodification of a procedure set forth in the literature (e.g., Ferritoet al., Macromol. Synth., 11, pp. 59-62 (1992)) in which diethylpropylmalonate was used instead of diethyl ethylmalonate. The procedureused was identical to that set forth in Example 1. Crude 2-propylacrylicacid (yellow oil) was vacuum distilled (b.p. 60° C./1 mm Hg) to yieldpure, colorless 2-Propylacrylic acid (35 gm).

Step II: Preparation of Poly(2-propylacrylic acid)

Distilled 2-Propylacrylic acid was placed in ampules and subjected tofour freeze-degas-thaw cycles and sealed under vacuum. AIBN (from 0.1-5mol %) was added and the polymerizations were carried out in bulk at 64°C. for 24 hours. The resulting slurry was dissolved in methanol andprecipitated into diethyl ether. The precipitated polymer was collectedby filtration, dissolved in pH 10 phosphate buffer, and dialyzed againstwater for several days in cellulose dialysis tubing (MWCO=1000).

Example 3 Conformational Properties of Poly(Carboxylic Acid)s

The conformational transition of a series of poly(carboxylic acid)s insolution was studied by observing the steady-state fluorescence ofcodissolved pyrene using procedures set forth in the literature (e.g.,Chen et al., J. Polym. Sci. Polym. Chem., 17, pp. 1103-1116 (1979)). Inthis study, a polymer stock solution of low buffer capacity was preparedby dissolving the poly(carboxylic acid) (4 mg/ml) and pyrene (200 μM) ina 5 mM buffer (phosphate or borate) of high enough pH for dissolution.Buffers of higher buffer capacity (100 mM) were prepared ranging in pHfrom 2.2 to 10.0 using either citric acid-phosphate, sodium and disodiumphosphate, or boric acid-borax buffering systems. Samples forfluorescence measurements were prepared by mixing 0.5 ml of thepolymer/pyrene stock solution with 1.5 ml of the higher buffer capacitysolutions at various solution pH, to give final concentrations of 1mg/mL of the poly(carboxylic acid) and 50 μM pyrene. Pyrene was excitedat 337 nm and the conformational transition was followed by measuringthe intensity of the fluorescence emitted at 373 nm (peak 1) and at 384nm (peak 3) using a PTI fluorescence spectrophotometer.

The series of poly(carboxylic acid)s studied were polyacrylic acid (PAA,MW=450,000, available from Polysciences, Inc., Warrington, Pa.),poly(methacrylic acid) (PMAA, MW=9,500 available from Aldrich Chemical,Milwaukee, Wis.], poly(2-ethylacrylic acid) (PEAA, MW=30,000) of Example1, and poly(2-propylacrylic acid) (PPAA, MW=9,000) of Example 2. In thisseries of poly(carboxylic acid)s, the substituent at the 2 positionprogressively becomes more hydrophobic going from a proton, to a methylgroup, to an ethyl group, to a propyl group. The results of theconformational transition study show the effect of the substituent groupon the conformational transition can be seen in FIG. 1. For PAA, thetransition midpoint is approximately at a pH of 4, and this transitionmidpoint shifts to higher pH's for the more hydrophobically modifiedpoly(carboxylic acid)s [PMAA=pH 5; PEAA=pH 6.25; and PPAA=pH 7.25]. Thisconformational transition can be correlated with the ionization of thepolymer where at higher pH's the chains are highly ionized and morehydrophilic (therefore showing a low fluorescence intensity in thepyrene assay) and at lower pH's the carboxylate groups along the polymerchain become protonated and the polymer chain collapsed to a morecompact coil, is more hydrophobic, and therefore more surface active aswell. This situation corresponds to the high fluorescence intensity inthe pyrene assay, where the pyrene is localized in the hydrophobiccollapsed coil.

Example 4 Treatment of Contact Lenses with Polyacid Solutions

Aqueous solutions containing the PAA, PMAA, PEAA, and PPAA described inExample 3 were prepared at a concentration of 0.5% by weight and thepH's were adjusted to 2.9, 3.2, 5.5, and 6.1 respectively. PureVision®contact lenses (Bausch & Lomb Incorporated, Rochester, N.Y., USA) madeof balafilicon A were rinsed in deionized water and placed in a lensvial along with 2.5 mL of the aforementioned aqueous solutions. The lensvials were then autoclaved for 30 minutes (121° C., 30 PSI). Aftercooling, the lenses were removed from the autoclave vials, rinsed bydipping into deionized water 10 times and placed in buffers of varyingpH (2.6-8.8) in scintillation vials. After thorough rinsing of thelenses at desired pH, the lenses were subjected to surface analysis.Alternatively, the lenses and solutions of this invention could beautoclaved while contained in a blister package sealed with lidstock.

Example 5 XPS Analysis of Coated Lenses

The PureVision® lenses treated with the four different poly(carboxylicacid)s [PAA, PMAA, PEAA, and PPAA] and thoroughly rinsed with varying pHbuffers (2.6-8.8) of Example 4 were analyzed using XPS. Three sectionsfrom both the anterior surface (side of lens facing air) and theposterior surface (side of lens in contact with eye) were analyzed. Theresults are summarized in FIGS. 2-4, which show the Carbon 1s (C1s)photoelectron region, the Oxygen 1s (O1s) photoelectron region, and thepercent silicone concentration in the XPS spectra, respectively. In FIG.2, the carbonyl carbon can be seen in the carbon 1s region of the XPSspectra at around 289 eV. This peak appears to be strongest for PAA andPMA, and weaker as you go to PEAA and PPAA which is expected since thenumber of carbons in the repeat unit of the poly(carboxylic acid)increases as you go from PMAA (4) to PEAA (5) to PPAA (6). In FIG. 3,the oxygen is region of the XPS spectra is shown. The peak that appearsat around 537 eV can be attributed to the —OH group of the carboxylicacid on the polyacids.

FIG. 4 shows the percent silicone in the XPS spectra of PureVision®lenses treated with the various poly(carboxylic acid)s that have beenthoroughly rinsed with buffers of various pH's after being autoclaved inthe polyacid solutions. The pH of the rinsing solution is noted in thefigure above each of the bars. The PureVision control is shown as solidblack bars. One can easily see that by examination of the percentsilicone in the XPS spectra that the PAA coating begins to rinse awayfrom the substrate at a pH of 6.0, PMAA begins to rinse away from thesubstrate at a pH of 6.6, while the PEAA and PPAA remain strongly bondedto the surface at pH's of 8.0 and 8.8 respectively. This datademonstrates that the more hydrophobically modified poly(carboxylicacid)s, i.e., PEAA and PPAA, are more difficult to rinse away from theunderlying lens substrates and are capable of covering the siliconesurface at pH ranges most desirable for a lens packaging solution (pH'sof 6.7-8.0).

Example 7 Contact Angle Analysis of Coated Lenses

Contact angle analysis was done on twenty lots of poly(carboxylic acid)coated lenses and one lot of control PureVision® lenses. The test lenseswere coated with PAA, PMAA, PEAA, or PPAA described in Example 3 at fivedifferent pH values for each coating. The lenses were removed from thebuffer solution and quartered using a clean scalpel. The quarters weremounted on a clean glass slide and dried overnight in a nitrogendry-box. Contact angles were measured on the dehydrated lenses at twopoints on each quarter. The instrument used for measurement was an ASTProducts Video Contact Angle System (VCA) 2500XE. This instrumentutilizes a low-power microscope that produces a sharply defined image ofthe water drop, which is captured immediately on the computer screen.HPLC water was drawn into the VCA system microsyringe, and a 0.6 μl dropis dispensed from the syringe onto the sample. The contact angle wascalculated by placing three to five markers along the circumference ofthe drop. The software calculates a curve representing the circumferenceof the drop and the contact angle was recorded. Both a right and leftcontact angle were reported for each measurement.

The results of the contact angle study are shown in FIG. 5. All of thelenses coated with the various poly(carboxylic acid) polymers have alower water contact angle (i.e., a more wettable lens surface) than thecontrol PureVision® lens. It is also interesting to note that ingeneral, as the hydrophobicity of the substituent in the 2 position wasincreased, there was an increase in the measured contact angle, possiblydue to the hydrophobic nature of the side chain. In addition, the samplethat showed silicone levels reapproaching the controls by XPS analysis(PAA at pH of 6.0 and PMAA at pH of 6.6) continue to have low contactangles, possibly due to the fact that little polymer need be present tosignificantly lower the contact angle when compared to the control.

It will be understood that various modifications may be made to theembodiments disclosed herein. Therefore the above description should notbe construed as limiting, but merely as exemplifications of preferredembodiments. For example, the functions described above and implementedas the best mode for operating the present invention are forillustration purposes only. Other arrangements and methods may beimplemented by those skilled in the art without departing from the scopeand spirit of this invention. Moreover, those skilled in the art willenvision other modifications within the scope and spirit of the featuresand advantages appended hereto.

1. A method for improving the wettability of a biomedical device, themethod comprising the step of contacting a surface of the biomedicaldevice with a composition comprising a polymer or copolymer having oneor more repeating units of the formula:

wherein R independently is a C₂-C₂₀ hydrocarbon radical and n is aninteger of 2 to
 5000. 2. The method of claim 1, wherein the biomedicaldevice is a contact lens.
 3. The method of claim 1, wherein thebiomedical device is a silicone hydrogel contact lens.
 4. The method ofclaim 1, wherein R is a C₂-C₆ straight chain or branched alkyl group. 5.The method of claim 1, wherein R is an ethyl or propyl group.
 6. Themethod of claim 1, wherein the polymer or copolymer is obtained from thepolymerization or copolymerization of a monomeric mixture comprising oneor more C₂-C₆ straight chain, branched, and cyclic 2-alpha-alkyl acrylicacids.
 7. The method of claim 6, wherein the monomeric mixture furthercomprises one or more hydrophilic monomers.
 8. A surface modifiedbiomedical device comprising a biomedical device having a coating on asurface thereof, the coating comprising a polymer or copolymer havingone or more repeating units of the formula:

wherein R independently is a C₂-C₂₀ hydrocarbon radical and n is aninteger of 2 to
 5000. 9. The surface modified biomedical device of claim8, wherein the biomedical device is a contact lens.
 10. The surfacemodified biomedical device of claim 8, wherein the biomedical device isa silicone hydrogel contact lens.
 11. The surface modified biomedicaldevice of claim 8, wherein R is a C₂-C₆ straight chain or branched alkylgroup.
 12. The surface modified biomedical device of claim 8, wherein Ris an ethyl or propyl group.
 13. The surface modified biomedical deviceof claim 8, wherein the polymer or copolymer is obtained from thepolymerization or copolymerization of a monomeric mixture comprising oneor more C₂-C₆ straight chain, branched, and cyclic 2-alpha-alkyl acrylicacids.
 14. The surface modified biomedical device of claim 13, whereinthe monomeric mixture further comprises one or more hydrophilicmonomers.